The present invention relates to a novel pyrrolidine compound having a potent 5-HT2 receptor antagonistic action and useful as a therapeutic agent for the diseases such as thrombotic embolism, chronic arterial obstruction, intermittent claudication, coronary artery disease, cerebrovascular disorder, peripheral circulatory disturbance, migraine, diabetic peripheral neuropathy, postherpetic neuralgia, glaucoma, dry eye, xerophthalmia, keratitis sicca and the like.
Serotonin (5-hydroxytryptamine; hereinafter to be referred to as 5-HT) dramatically enhances platelet aggregation due to collagen, epinephrine and adenosine diphosphate (hereinafter to be referred to as ADP). A serotonin 2 (hereinafter to be referred to as 5-HT2) receptor is involved in the promotion of platelet aggregation, erythrocyte deformation, vasoconstriction and blood vessel permeability. Since collateral circulation associated with high 5-HT sensitivity is developed in chronic arterial obstruction, blocking of 5-HT2 receptor should improve the peripheral circulation because it induces vasodilation at the site of lesion rather than systemic one. In view of the above, a 5-HT2 receptor antagonist has been searched and, for example, (3-aminopropoxy)bibenzyl derivative having a platelet aggregation inhibitory activity and usable for the treatment and prevention of thrombosis is disclosed in JP-B-63-13427. In addition, reports have documented that sarpogrelate hydrochloride, which is a selective antagonist to a 5-HT2 receptor, is effective on migraine (J. New Remedies and Clinics, Vol. 45(9), pp. 1833-1836, 1996), on diabetic peripheral neuropathy (Jpn. Pharmacol. Ther., Vol. 24(8), pp. 1853-1857, 1996), and on postherpetic neuralgia (Jpn. Pharmacol. Ther., Vol. 23(7), pp. 1803-1806, 1995). However, the platelet aggregation suppressive action and vasoconstriction suppressive action are not entirely satisfactory and a compound having more superior activity has been demanded.
Moreover, JP-A-8-20531 discloses that 5-HT2 receptor antagonists, inclusive of sarpogrelate hydrochloride, are effective for the treatment of glaucoma and diminished ocular tension, and JP-A-10-67684 discloses that 5-HT2 receptor antagonists, inclusive of sarpogrelate hydrochloride, have a lacrimation promoting action and are effective for the treatment of diseases such as dry eye, xerophthalmia, keratitis sicca and the like.
JP-B-49-31985 discloses a compound having a similar structure to the novel pyrrolidine compound of the present invention. It also discloses a 1-substituted-3-amidopyrrolidine derivative having an analgesic and antidepressant action. Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 10(6), pp. 1015-1021, 1967 discloses an N-substituted-3-amidopyrrolidine derivative as a synthetic intermediate for an aminoalkylindole derivative as a centrally acting drug. Japanese Patent Application under PCT laid-open under Kohyo No. 7-506110 discloses a preparation method of (S)-3-amino-1-substituted-pyrrolidine. JP-A-3-95157 discloses a butenoic acid derivative as a therapeutic agent of coronary artery disease. JP-A-1-316349 discloses a preparation method of (S)-3-aminopyrrolidine and a production method of naphthyridine and quinolonecarboxylic acid having (S)-3-aminopyrrolidine as a side chain. Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 11(5), pp. 1034-1037, 1968, U.S. Pat. Nos. 3,424,760, 3,424,761 and 3,424,762 disclose 3-ureidopyrrolidine derivatives having an analgesic and central action. However, these do not take note of the 5-HT2 receptor antagonistic action or a platelet aggregation inhibitory activity.
The present invention aims at providing a novel compound having a 5-HT2 receptor antagonistic action, a platelet aggregation suppressive action and a peripheral circulation improving action and/or a novel compound having a lacrimation promoting action.
The present inventors have conducted intensive studies and found that a novel pyrrolidine compound of the following formula (I), an optically active compound thereof and a pharmaceutically acceptable salt thereof have a strong 5-HT2 receptor antagonistic action along with a platelet aggregation suppressive action, a peripheral circulation improving action and a lacrimation promoting action. As such, the compound of the present invention can be useful for the treatment of diseases such as thrombotic embolism, chronic arterial obstruction, intermittent claudication, coronary artery disease, cerebrovascular disorder, peripheral circulatory disturbance, migraine, diabetic peripheral neuropathy, postherpetic neuralgia, glaucoma, dry eye, xerophthalmia, keratitis sicca and the like.
Accordingly, the present invention provides the following.
[1] A pyrrolidine compound of the formula (I) 
wherein
R1 is a group selected from the groups of the following formulas (1), (2), (3), (4), (5), (6), (7) and (8) 
wherein
R3 and R4 are the same or different and each is hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, amino, dialkylamino, nitro, cyano, amido, or R3 and R4 in combination form carbonyl,
R5, R6, R7 and R8 are the same or different and each is hydrogen or alkyl, or R5xe2x80x94R6 and R7xe2x80x94R8 are the same or different and each is bonded to form, together with the bond between the carbon atoms they are bonded to, a double bond, optionally substituted cycloalkyl having 3 to 8 carbon atoms, optionally substituted cycloalkenyl having 3 to 8 carbon atoms, optionally substituted cycloalkadienyl having 5 to 8 carbon atoms, optionally substituted aromatic ring or optionally substituted aromatic heterocycle having, as a heteroatom, at least one atom selected from oxygen atom, nitrogen atom and sulfur atom,
ring A and ring B are the same or different and each is optionally substituted cycloalkyl having 3 to 8 carbon atoms, optionally substituted cycloalkenyl having 3 to 8 carbon atoms, optionally substituted cycloalkadienyl having 5 to 8 carbon atoms, optionally substituted aromatic ring or an optionally substituted aromatic heterocycle having at least one atom selected from oxygen atom, nitrogen atom and sulfur atom as a heteroatom,
ring H is optionally substituted cycloalkyl having 3 to 8 carbon atoms,
E is optionally substituted cycloalkyl having 3 to 8 carbon atoms,
Z is carbon atom, nitrogen atom or N-oxide,
Y may not be present to make the ring A and ring B independent, or a single bond, oxygen atom, sulfur atom, SO, SO2, CH2, CH2CH2 or CHxe2x95x90CH,
p, q, r, s, t and u are the same or different and each is an integer of 1 or 2,
uxe2x80x2 is an integer of 0-2,
rxe2x80x2 and sxe2x80x2 are the same or different and each is an integer of 0-3, and
v, w and x are the same or different and each is an integer of 1-3,
R9 is hydrogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms or hydroxyalkyl having 1 to 6 carbon atoms,
x is Cxe2x95x90O, Cxe2x95x90S, NHxe2x80x94Cxe2x95x90O, SO or SO2,
R2 is hydrogen, alkyl, acyl, optionally substituted arylalkyl, optionally substituted aromatic ring, or an optionally substituted aromatic heterocycle having at least one atom selected from oxygen atom, nitrogen atom and sulfur atom as a heteroatom,
D is optionally substituted linear or branched alkylene having 1 to 8 carbon atoms, and when D is branched alkylene, the carbon atom in the branched chain is optionally bonded further to Ar to form 4- to 8-membered ring, and
Ar is optionally substituted aromatic ring, optionally substituted aromatic heterocycle or fused aromatic heterocycle having at least one atom selected from oxygen atom, nitrogen atom and sulfur atom as a heteroatom,
provided that
when X is NHxe2x80x94Cxe2x95x90O, SO or SO2, R2 should be hydrogen, alkyl, optionally substituted arylalkyl, optionally substituted aromatic ring or optionally substituted aromatic heterocycle having at least one atom selected from oxygen atom, nitrogen atom and sulfur atom as a heteroatom,
when R1 is a group of the formula (5) to formula (7), X should be Cxe2x95x90O or Cxe2x95x90S and R2 should be hydrogen or alkyl, and
when R1 is a group of the formula (5), D should be optionally substituted linear or branched alkylene having 2 to 8 carbon atoms, and when D is branched alkylene, the carbon atom in the branched chain is optionally bonded further to Ar to form 4- to 8-membered ring
or an optically active compound thereof or a pharmaceutically acceptable salt thereof.
[2] The pyrrolidine compound of the above-mentioned [1], wherein, in the formula (I), R1 is a group of the formula (1), (3), (6) or (7), an optically active compound thereof or a pharmaceutically acceptable salt thereof.
[3] The pyrrolidine compound of the above-mentioned [1], wherein, in the formula (I), X is Cxe2x95x90O, NHxe2x80x94Cxe2x95x90O, SO or SO2, an optically active compound thereof or a pharmaceutically acceptable salt thereof.
[4] The pyrrolidine compound of the above-mentioned [1], wherein, in the formula (I), R1 is a group of the formula (1), X is Cxe2x95x90O, R2 is hydrogen, D is ethylene or trimethylene, Ar is optionally substituted aromatic ring or optionally substituted aromatic heterocycle or fused aromatic heterocycle having at least one atom selected from oxygen atom, nitrogen atom and sulfur atom as a heteroatom, R3 and R4 are the same or different and each is hydrogen or alkyl, or R3 and R4 in combination form carbonyl, p, q, r, s, t and u are 1, and Z is carbon atom, an optically active compound thereof or a pharmaceutically acceptable salt thereof.
[5] The pyrrolidine compound of the above-mentioned [1], which is selected from
(S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide,
(S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide,
(S)-N-(1-(2-(3-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide,
(S)-N-(1-(2-(2-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide,
(S)-N-(1-(3-phenylpropyl)pyrrolidin-3-yl )-1-adamantanecarboxamide,
(S)-N-(1-(3-(4-fluorophenyl)propyl)pyrrolidin-3-yl)-1-adamantanecarboxamide,
(S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)dicyclohexylacetamide,
(S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)dicyclohexylacetamide,
(S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-10,11-dihydrodibenzo[a,d]cycloheptene-5-carboxamide,
(S)-1,1-dicyclohexyl-3-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)urea,
N-methyl-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-1-adamantanecarboxamide, and
(S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-(4-azatricyclo[4.3.1.1(3,8)]undecan-4-yl)carboxamide or a pharmaceutically acceptable salt thereof.
[6] A pharmaceutical composition comprising the pyrrolidine compound of the above-mentioned [1], an optically active compound thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
[7] A pharmaceutical agent comprising the pyrrolidine compound of the above-mentioned [1], an optically active compound thereof or a pharmaceutically acceptable salt thereof.
[8] A 5-HT2 receptor antagonist comprising the pyrrolidine compound of the above-mentioned [1], an optically active compound thereof or a pharmaceutically acceptable salt thereof.
[9] A platelet aggregation suppressant comprising the pyrrolidine compound of the above-mentioned [1], an optically active compound thereof or a pharmaceutically acceptable salt thereof.
[10] A lacrimation promoter comprising the pyrrolidine compound of the above-mentioned [1], an optically active compound thereof or a pharmaceutically acceptable salt thereof.
[11] A therapeutic agent for arterial obstruction, antithrombotic drug or peripheral circulation disorder ameliorating agent, which comprises the pyrrolidine compound of the above-mentioned [1], an optically active compound thereof or a pharmaceutically acceptable salt thereof.
In the above-mentioned formula (I), each group is concretely exemplified by the following.
The alkyl at R2 to R9 is linear or branched alkyl having 1 to 18 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, decyl, hexadecyl, octadecyl and the like, with preference given to that having 1 to 6 carbon atoms.
The acyl at R2 is, for example, alkanoyl, arylalkanoyl, aroyl, heteroarylcarbonyl and the like. More specifically, alkanoyl is linear or branched alkanoyl having 1 to 6 carbon atoms, which is, for example, formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, hexanoyl and the like. The alkanoyl moiety of arylalkanoyl is as mentioned above, which is, for example, benzylcarbonyl, 3-phenylpropionyl, 4-phenylbutyryl and the like. Examples of aroyl include benzoyl, toluoyl, xyloyl, salicyloyl, cinnamoyl, naphthoyl and the like. Examples of heteroarylcarbonyl include furoyl, nicotinoyl, isonicotinoyl, thenoyl and the like, with preference given to acetyl, propionyl, butyryl, benzylcarbonyl, 3-phenylpropionyl, benzoyl, p-toluoyl and the like.
The optionally substituted arylalkyl at R2 consists of alkyl having 1 to 6 carbon atoms and optionally substituted phenyl. Examples thereof include benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like. Examples of the substituent include (a) halogen such as fluorine, chlorine, bromine, iodine and the like, (b) alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like, (c) alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like, (d) haloalkyl having 1 to,6 carbon atoms such as fluoro-methyl, difluoromethyl, trifluoromethyl and the like, (e) hydroxy, (f) amino, (g) dialkylamino having two same or different alkyl having 1 to 6 carbon atoms, such as dimethylamino, diethylamino, N-methyl-N-ethylamino and the like, (h) nitro, (i) cyano, and (j) amidino optionally substituted by one or more alkyl having 1 to 6 carbon atoms and the like.
The optionally substituted aromatic ring at R2, ring A, ring B, Ar, and R5xe2x80x94R6 and R7xe2x80x94R8, which are respectively bonded together with the bond between the carbon atoms they are bonded to, is, for example, phenyl, naphthyl, 2-indanyl and the like. Examples of the substituent include the aforementioned (a)-(j) and the like.
The optionally substituted aromatic heterocycle having at least one atom selected from oxygen atom, nitrogen atom and sulfur atom as a heteroatom at R2, ring A, ring B, Ar, and R5xe2x80x94R6 and R7xe2x80x94R8, which are respectively bonded together with the bond between the carbon atoms they are bonded to, is, for example, pyridyl, furyl, thienyl, pyrimidinyl and the like. Examples of the substituent include the aforementioned (a)-(j) and the like.
The halogen at R3 and R4 is, for example, fluorine, chlorine, bromine, iodine and the like.
The alkoxy at R3, R4 and R9 is that having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.
The haloalkyl at R3 and R4 is that having 1 to 6 carbon atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl and the like.
The dialkylamino at R3 and R4 is that having two same or different alkyl having 1 to 6 carbon atoms, such as dimethylamino, diethylamino, N-methyl-N-ethylamino and the like.
The amido at R3 and R4 is a group consisting of acyl at R2 and amino, such as formamido, acetamido, propanamido, butanamido, cyclohexanecarbonylamino, benzamido, benzylcarbonylamino and the like.
The hydroxyalkyl at R9 is that having 1 to 4 carbon atoms, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and the like.
The optionally substituted cycloalkyl having 3 to 8 carbon atoms at ring A, ring B, ring H, E, and R5xe2x80x94R6 and R7xe2x80x94R8, which are respectively bonded together with the bond between the carbon atoms they are bonded to, is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Examples of the substituent include the aforementioned (a)-(j) and the like.
The optionally substituted cycloalkenyl having 3 to 8 carbon atoms at ring A, ring B, and R5xe2x80x94R6 and R7xe2x80x94R8, which are respectively bonded together with the bond between the carbon atoms they are bonded to, is, for example, that wherein one hydrogen molecule left the above-mentioned cycloalkyl to make one double bond in the ring. Examples thereof include 2-cyclopentenyl, 2-cyclohexenyl, 2-cycloheptenyl, 2-cyclooctenyl and the like. Examples of the substituent include the aforementioned (a)-(j) and the like.
The optionally substituted cycloalkadienyl having 5 to 8 carbon atoms at ring A, ring B, and R5xe2x80x94R6 and R7xe2x80x94R8, which are respectively bonded together with the bond between the carbon atoms they are bonded to, is, for example, that wherein two hydrogen molecules left the above-mentioned cycloalkyl to make two double bonds in the ring, which double bonds being optionally conjugated. Examples thereof include cyclopentadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,4-cycloheptadienyl, 1,3-cyclooctadienyl, 1,4-cyclooctadienyl, 1,5-cyclooctadienyl and the like. Examples of the substituent include the aforementioned (a)-(j) and the like.
The optionally substituted fused aromatic heterocycle having at least one atom selected from oxygen atom, nitrogen atom and sulfur atom as a heteroatom at Ar is a fused structure wherein aromatic heterocycle and aromatic ring or aromatic heterocycle share part of each ring. Examples thereof include 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, indol-3-yl, 1-benzofuran-3-yl, 1-benzothiophen-3-yl and the like. Examples of the substituent include the aforementioned (a)-(j) and the like.
The optionally substituted linear or branched alkylene having 1 to 8 carbon atoms at D is, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, octamethylene, methylmethylene, dimethylmethylene, 1-methylethylene, 2-methylethylene, 1,1-dimethylethylene, 2,2-dimethylethylene, ethylmethylene, diethylmethylene, 1-ethylethylene, 2-ethylethylene, 1-methyltrimethylene, 1,1-dimethyltrimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 3-methyltrimethylene, 3,3-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 3-ethyltrimethylene and the like. Examples of the substituent include (a) alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like, (b) hydroxy, (c) acyloxy having 2 to 6 carbon atoms, such as acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy and the like, (d) xe2x80x94Oxe2x80x94(CH2)lxe2x80x94COOH wherein l is an integer of 1-5, such as xe2x80x94Oxe2x80x94(CH2)2xe2x80x94COOH, xe2x80x94Oxe2x80x94(CH2)3xe2x80x94COOH and the like, (e) xe2x80x94Oxe2x80x94COxe2x80x94(CH2)mxe2x80x94COOH wherein m is an integer of 1-3, such as xe2x80x94Oxe2x80x94COxe2x80x94(CH2)2xe2x80x94COOH, xe2x80x94Oxe2x80x94COxe2x80x94(CH2)3xe2x80x94COOH and the like, and the like.
When D is branched alkylene, the carbon atom in the branched chain is further bonded to Ar to form a 4- to 8-membered ring. Specifically, when Ar is phenyl, D and Ar in combination form (2,3-dihydroinden-2-yl)methyl, (2,3-dihydroinden-2-yl)ethyl, (2,3-dihydroinden-1-yl)methyl, 2,3-dihydroinden-2-yl, (1,2,3,4-tetrahydro-1-naphthyl)methyl, (1,2,3,4-tetrahydro-2-naphthyl)methyl, (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)methyl and the like. The same applies to the case where Ar is aromatic heterocycle or fused aromatic heterocycle having at least one atom selected from oxygen atom, nitrogen atom and sulfur atom as a heteroatom.
The ring A and ring B are the same or different and each is preferably phenyl, cyclopentyl, cyclohexyl or cycloheptyl.
It is preferable that Y be not present and make ring A and ring B independent, a single bond, CH2CH2 or CHxe2x95x90CH.
The particularly preferable substituent for the compound of the present invention is exemplified by the following.
That is,
R1 preferably has the formula (1), the formula (3), the formula (6) or the formula (7), with more preference given to the formula (1).
X is preferably Cxe2x95x90O, Cxe2x95x90S, NHxe2x80x94Cxe2x95x90O, SO or SO2, with particular preference given to Cxe2x95x90O.
R2 is preferably hydrogen or alkyl, with more preference given to hydrogen.
D is preferably alkylene having 2 or 3 carbon atoms, which is specifically ethylene or trimethylene. When D is branched alkylene, and the carbon atom in the branched chain is further bonded to Ar to form a 4- to 8-membered ring, D and Ar in combination preferably form (2,3-dihydroinden-2-yl)methyl, (2,3-dihydroinden-2-yl)ethyl, (1,2,3,4-tetrahydro-1-naphthyl)methyl, (1,2,3,4-tetrahydro-2-naphthyl)methyl and (6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)methyl.
Ar is preferably phenyl. Examples of the preferable substituent include chlorine atom and fluorine atom, and the number of the substituent is preferably 1 or 2.
Z is preferably carbon atom.
When R1 is expressed by the formula (1), the following formula (9) is preferable 
wherein the following formula (10) is particularly preferable 
When R1 is expressed by the formula (3), the following formula (11) is particularly preferable 
When R1 is expressed by the formula (6), the following formula (12) or (13) is preferable 
wherein the following formula (14) is particularly preferable 
When R1 is expressed by the formula (7), the following formula (15), (16), (17) or (18) is preferable 
The pharmaceutically acceptable salt of the compound of the formula (I) is exemplified by an acid addition salt with an inorganic acid (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like) or an organic acid (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, ascorbic acid and the like). It is also possible to convert the compound to oxalate for crystallization thereof.
The compound of the formula (I) and a pharmaceutically acceptable salt thereof may be present in the form of a hydrate or a solvate. Thus, hydrates (1/2 hydrate, 1/3 hydrate, 1 hydrate, 3/2 hydrate, 2 hydrate, 3 hydrate and the like) and solvates of these are also encompassed in the present invention. The compound of the formula (I) has at least two kinds of optically active compounds. The optically active compounds thereof are also encompassed in the present invention.
The compound of the present invention encompassed in the formula (I) can be synthesized by, for example, the following method. In the formula, each symbol means the same as defined above, unless particularly indicated otherwise.
1. When R1 is expressed by the formulas (1)-(4) 
This Synthesis Method is suitable for the synthesis of a compound of the formula (I) wherein X is Cxe2x95x90O and R2 is hydrogen. A compound of the formula (1) wherein J is amine protecting group (e.g., benzyl, tert-butyloxycarbonyl, benzyloxycarbonyl and the like) generally used in organic synthetic chemistry and a compound of the formula (2) are reacted in a solvent that does not interefere with the progress of the reaction (methylene chloride, chloroform, ethylene dichloride, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), or an optionally mixed solvent thereof and the like), in the presence of a base (triethylamine, diisopropylethylamine and the like) generally used in organic synthetic chemistry, from under cooling to refluxing temperature of solvent (preferably 0xc2x0 C.xe2x80x94room temperature) by adding a condensing agent generally used in organic synthetic chemistry for amine and carboxylic acid (diethyl cyanophosphate, 1,3-dicyclohexylcarbodiimide (DCCD), 1-ethyl-3-(3xe2x80x2-dimethylaminopropyl)carbodiimide (WSCI), benzotriazolyl-N-hydroxytrisdimethylaminophosphonium hexafluorophosphate (Bop reagent) and the like) to give a compound of the formula (3). These reactions generally end in 24 hours.
This compound of the formula (3) can be obtained by once introducing the compound of the formula (2) into carboxylic acid halide, imidazole amide and the like and reacting this compound and a compound of the formula (1) in the presence of a base (triethylamine, diisopropylethylamine and the like) generally used in organic synthetic chemistry, at a temperature of from under cooling to the refluxing temperature of the solvent (preferably 0xc2x0 C.xe2x80x94room temperature). These reactions generally end in 24 hours.
Furthermore, it can be obtained by reacting a compound of the formula (2) in a solvent that does not interfere with the progress of the reaction (methylene chloride, chloroform, ethylene dichloride, acetonitrile, THF, ethyl acetate, toluene, tert-butyl alcohol, dimethoxyethane, DMF, or an optionally mixed solvent thereof and the like), in the presence of a base (triethylamine, diisopropylethylamine and the like) generally used in organic synthetic chemistry, at a temperature of from under cooling to the refluxing temperature of the solvent (preferably xe2x88x9210xc2x0 C. to 5xc2x0 C.), with acid chloride (pivaloyl chloride, ethyloxycarbonyl chloride, isobutyloxycarbonyl chloride (IBCF) and the like) generally used in organic synthetic chemistry to give a mixed acid anhydride, and adding a compound of the formula (1) to allow reaction. These reactions generally end in 24 hours.
Then, the amino protecting group of the compound of the formula (3) is subjected to deprotection under the conditions (4 mol/L hydrochloric acid-dioxane, trifluoroacetic acid, hydrogen-palladium carbon, hydrobromic acid-acetic acid and the like) generally used in organic synthetic chemistry to give a compound of the formula (4). These reactions generally end in 24 hours.
The compound of the formula (4) and a compound of the formula (5), wherein E is a leaving group generally used in organic synthetic chemistry, such as methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy, chlorine atom, bromine atom, iodine atom and the like, is reacted without solvent or in a solvent that does not interfere with the progress of the reaction (toluene, acetonitrile, THF, DMF, DMSO, water or an optionally mixed solvent thereof and the like) generally used in organic synthetic chemistry, in the presence of a base (triethylamine, diisopropylethylamine, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, sodium hydride, potassium tert-butoxide and the like) generally used in organic synthetic chemistry, at a temperature of from under cooling to the refluxing temperature of the solvent to give the objective compound, the compound of the formula (6). These reactions generally end in 24 hours.
The hydrogen at R2 can be converted to various substituents by reaction generally used in organic synthetic chemistry. 
The compound of the formula (6) can be also synthesized by the following method.
A compound of the formula (7) and a compound of the formula (5) are reacted for alkylation of amine as in Synthesis Method 1 to give a compound of the formula (8).
The amino protecting group of this compound is subjected to deprotection according to the deprotection method as in Synthesis Method 1 to give a compound of the formula (9).
The compound of the formula (9) and the compound of the formula (2) are reacted according to a condensation method of carboxylic acid and amine as in Synthesis Method 1 to give the objective compound, the compound of the formula (6). 
This Synthesis Method is suitable for the synthesis of a compound wherein, in the formula (I), D has 2 or more carbon atoms.
A compound of the formula (7) and a compound of the formula (10), wherein G is linear or branched alkylene having 1 to 7 carbon atoms, are reacted according to a condensation method of carboxylic acid and amine as in Synthesis Method 1 to give a compound of the formula (11).
By deprotection of the amino protecting group of the compound of the formula (11) by a deprotection method as in Synthesis Method 1, a compound of the formula (12) is obtained.
A compound of the formula (12) is reacted in a solvent that does not interfere with the progress of the reaction (diethyl ether, diisopropyl ether, 1,4-dioxane, THF and the like) generally used in organic synthetic chemistry, with a reducing agent (lithium aluminum hydride, diisobutylaluminum hydride, borane (BH3) and the like) generally used in organic synthetic chemistry at xe2x88x9278xc2x0 C. to the refluxing temperature of the solvent to give a compound of the formula (13). These reactions generally end in 24 hours.
The compound of the formula (13) and the compound of the formula (2) are reacted according to the condensation method of carboxylic acid and amine as in Synthesis Method 1 to give the objective compound, the compound of the formula (14). 
This Synthesis Method is suitable for the synthesis of a compound wherein, in the formula (I), X is Cxe2x95x90O and R2 is not hydrogen. The amino protecting group of a compound of the formula (15) obtained according to the method described in Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 10, p. 1015 (1967) is deprotected according to the deprotection method as in Synthesis Method 1 to give a compound of the formula (16).
The compound of the formula (16) and the compound of the formula (5) are reacted for alkylation of amine as in Synthesis Method 1 to give a compound of the formula (17).
The compound of the formula (17) and the compound of the formula (2) are reacted according to the condensation method of carboxylic acid and amine as in Synthesis Method 1 to give the objective compound, a compound of the formula (18). 
This Synthesis Method is suitable for the synthesis of a compound of the formula (I) wherein D has two or more carbon atoms.
The compound of the formula (16) and the compound of the formula (10) are reacted according to the condensation method for carboxylic acid and amine as in Synthesis Method 1 to give a compound of the formula (19).
The compound of the formula (19) is reduced according to the reduction method of amide as in Synthesis Method 3 to give a compound of the formula (20).
The compound of the formula (20) and the compound of the formula (2) are reacted according to the condensation method for carboxylic acid and amine as in Synthesis Method 1 to give a compound of the formula (21). 
This Synthesis Method is suitable for the synthesis of a compound wherein, in the formula (I), X is NHxe2x80x94Cxe2x95x90O and R2 is hydrogen.
A compound of the formula (22) is dissolved in a solvent that does not interfere with the progress of the reaction (THF, toluene and the like) and 1,1xe2x80x2-carbonylbis-1H-imidazole (CDI) is added. The mixture is reacted at a temperature of from under cooling to the refluxing temperature of the solvent (preferably 0xc2x0 C.xe2x80x94room temperature) and the compound of the formula (9) is added. The mixture is reacted at a temperature of from under cooling to the refluxing temperature of the solvent to give the objective compound, a compound of the formula (23).
The compound of the formula (23) can be also obtained by converting one of a compound of the formula (22) and a compound of the formula (9) according to the method generally used in organic synthetic chemistry to isocyanate and reacting the isocyanate with the other compound. 
This Synthesis Method is suitable for the synthesis of a compound wherein, in the formula (I), X is SO2 and R2 is hydrogen. The compound of the formula (9) and a compound of the formula (24) are reacted in a solvent that does not interfere with the progress of the reaction (methylene chloride, chloroform, ethylene dichloride, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF) or an optionally mixed solvent thereof and the like), in the presence of a base (triethylamine, diisopropylethylamine and the like) generally used in organic synthetic chemistry, at a temperature of from under cooling to the refluxing temperature of the solvent (preferably 0xc2x0 C.xe2x80x94room temperature) to give the objective compound, a compound of the formula (25). 
The compound of the formula (14) can be also synthesized by the following method. The compound of the formula (4) and a compound of the formula (26) are reacted in a solvent that does not interfere with the progress of the reaction (methanol, ethanol, propanol, isopropanol, butanol, methylene chloride, chloroform, ethylene dichloride, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), or an optionally mixed solvent thereof and the like), at a temperature of from under cooling to the refluxing temperature of the solvent (preferably 0xc2x0 C.xe2x80x94room temperature) for 0.1-24 hr. To the reaction mixture is added a reducing agent (sodium borohydride, sodium cyanoborohydride and the like) generally used in organic synthetic chemistry, at a temperature of from under cooling to the refluxing temperature of the solvent (preferably 0xc2x0 C.xe2x80x94room temperature), and the mixture is reacted at a temperature of from under cooling to the refluxing temperature of the solvent to give the objective compound, a compound of the formula (14).
2. When R1 is expressed by the formulas (5)-(7). 
This Synthesis Method is suitable for the synthesis of a compound wherein, in the formula (I), X is Cxe2x95x90O and R2 is hydrogen. A compound of the formula (27) is dissolved in a solvent that does not interfere with the progress of the reaction (THF, toluene and the like) and 1,1xe2x80x2-carbonylbis-1H-imidazole (CDI) is added. The mixture is reacted at a temperature of from under cooling to the refluxing temperature of the solvent (preferably 0xc2x0 C.xe2x80x94room temperature) and a compound of the formula (9) is added. The mixture is reacted at a temperature of from under cooling to the refluxing temperature of the solvent to give a compound of the formula (28).
The compound of the formula (28) can be also obtained by converting the compound of the formula (9) to isocyanate by a method generally used in organic synthetic chemistry and then reacting the isocyanate with the compound of the formula (27).
The hydrogen at R2 can be converted to various substituents by a reaction generally used in organic synthetic chemistry. The amine compound inclusive of the compound of the formula (1), and a carboxylic acid compound inclusive of the compound of the formula (2) and the like, which are synthetic starting materials, are known compounds or can be derived easily from known compounds by the reaction generally used in organic synthetic chemistry.
The compound of the present invention thus obtained can be isolated and purified by a conventional method such as recrystallization, column chromatography and the like. When the obtained product is a racemate, it can be resolved into desired optically active compounds by, for example, fractional recrystallization using an optically active acid or passing the racemate through a column packed with an optically active carrier. Each diastereomer can be separated by fractional crystallization, chromatography and the like. In addition, an optically active compound can be also obtained by the use of an optically active starting material compound and the like. The stereoisomer can be separated by recrystallization, column chromatography and the like.
When a pyrrolidine compound of the present invention, an optically active compound thereof and a pharmaceutically acceptable salt thereof are used as medicines, these are mixed with a carrier acceptable for the preparation of formulations (excipient, binder, disintegrant, flavor, corrective, emulsifier, diluent, solubilizer and the like) to give a pharmaceutical composition or a pharmaceutical preparation (tablet, pill, capsule, granule, powder, syrup, emulsion, elixir, suspension, solution, injection, transfusion, suppository and the like), which can be administered orally or parenterally. A pharmaceutical composition can be prepared into a formulation by a general method. As used in this specification, xe2x80x9cparenterallyxe2x80x9d includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, transfusion and the like.
A preparation for injection, such as an aqueous suspension or oily suspension for sterile injection, can be prepared using a suitable suspending agent or a wetting agent and a suspending agent according to a method known in this field. The preparation for sterile injection may be a sterile injectable solution or suspension using, for example, a non-toxic diluent or solvent that can be administered parenterally, such as an aqueous solution and the like. Examples of usable vehicle and acceptable solvent include water, Ringer""s solution, isotonic saline and the like. Furthermore, a sterile non-volatile oil can be generally used as a solvent or a suspending solvent. Any non-volatile oil or fatty acid can be used for this end, which includes natural or synthetic or semi-synthetic fatty oil or fatty acid, and natural or synthetic or semi-synthetic mono- or di- or triglycerides.
The suppository for rectal administration can be produced by mixing a drug with a suitable non-irritative excipient, such as cacao butter, polyethylene glycols and the like, which are solid at ordinary temperature but liquid at a rectal temperature and which dissolves in the rectum to release the drug.
The dosage form of a solid for oral administration is powder, granule, tablet, pill, capsule and the like as mentioned above. In such dosage forms, an active ingredient compound can be mixed with at least one additive, such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides and the like. The preparations in these dosage forms can contain a further additive as usual, such as inert diluents, lubricants (e.g., magnesium stearate and the like), preservatives (e.g., p-hydroxybenzoates, sorbates and the like), antioxidants (e.g., ascorbic acid, xcex1-tocopherol, cysteine and the like), disintegrants, binders, thickeners, buffering agents, sweeteners, flavors, perfumes and the like. Tablets and pills are produced by further applying an enteric coating. A liquid for oral administration may be pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which may contain an inert diluent generally used in this field, such as water.
The pyrrolidine compound of the present invention, an optically active compound thereof and a pharmaceutically acceptable salt thereof have a strong 5-HT2 receptor antagonistic action, and simultaneously show a platelet aggregation suppressive action, a peripheral circulation improving action, and a lacrimation promoting action. Thus, the compound of the present invention is effective as a therapeutic agent for the diseases such as thrombotic embolism, chronic arterial obstruction, intermittent claudication, coronary artery disease, cerebrovascular disorder, peripheral circulatory disturbance, migraine, diabetic peripheral neuropathy, postherpetic neuralgia, glaucoma, dry eye, xerophthalmia, keratitis sicca and the like.
The administration dose is determined depending on age, body weight, general health conditions, sex, diet, administration time, administration method, clearance rate, combination of drugs, severity of the disease for which the patient is undergoing treatments, and other factors. The compound of the present invention, an optically active compound thereof and a pharmaceutically acceptable salt thereof are low-toxic and can be used safely. The daily dose varies depending on the disease state and body weight of the patient, the kind of the compound, administration route and the like. For example, it is desirably about 0.01-50 mg/patient/day, preferably 0.01-20 mg/patient/day, for parenteral administration by subcutaneous, intravenous, intramuscular or rectal administration, and about 0.01-150 mg/patient/day, preferably 0.1-100 mg/patient/day, for oral administration.